This invention relates generally to expandable intraluminal vascular grafts, commonly referred to as stents, and more particularly pertains to the coating of stents in order to prevent acute thrombogenesis.
Stents are implanted within vessels in an effort to maintain the patency thereof by preventing collapse and/or impeding restenosis. Implantation of a stent is typically accomplished by mounting the stent on the expandable portion of a balloon catheter, maneuvering the catheter through the vasculature so as to position the stent at the treatment site within the body lumen, and inflating the balloon to expand the stent so as to engage the lumen wall. The stent automatically locks into its expanded configuration allowing the balloon to be deflated and the catheter to be removed to complete the implantation procedure. The use of self-expanding stents obviates the need for a balloon delivery device. Instead, a constraining sheath that is initially fitted about the stent is simply retracted once the stent is in position adjacent the treatment site.
A significant concern associated with the implantation of a stent within the vasculature is the potential for restenosis and thrombogenesis which may in fact be exacerbated by the presence of the stent. The pressure exerted by the stent on the vessel wall may increase the trauma that induces hyperplasia and the presence of the stent in the blood stream may induce a local or even systemic activation of the patient""s hemostase coagulation system. Bound proteins of blood plasma, principally the adhesive proteins such albumin, fibronectin, fibrinogen and fibrin, are known to trigger coagulation. The result is typically the adhesion and aggregation of thrombocytes on the surface of the stent. These proteins include peptide structures, e.g. the RGD-peptides composed of amino acids, such as glycine, arginine and asparagine. The same structures are involved in the adhesion of thrombocytes as a consequence of receptors of the thrombocyte surface, e.g. collagen, von WilleBrand factor and fibrin interactions. The same result may arise with other biomaterials, generally of metal or plastic composition, which are inserted temporarily or implanted permanently in the patient. The deposit of blood clots on the surface of the biomaterial can result from a complex reaction of plasmatic and cellular mechanisms of coagulation that enhance and influence each other. Thus, the implantation of a stent to keep the lumen of the artery open may only hasten re-occlusion by promoting localized blood clotting and reactive inflammation. Indeed, studies indicate that stents and other untreated biomaterials can be covered with a relatively thick thrombus formation only minutes after contact with blood.
Various pharmacological agents have heretofore been used to address the problem both on a systemic as well as localized level. The latter approach is most often preferred and it has been found convenient to utilize the implanted stent for such purpose wherein the stent serves both as a support for the lumen wall as a well as delivery vehicle for the pharmacological agent. However, the metallic materials typically employed in the construction of stents in order to satisfy the mechanical strength requirements are not generally capable of carrying and releasing drugs. On the other hand, while various polymers are known that are quite-capable of carrying and releasing drugs, they generally do not have the requisite strength characteristics. Moreover, the structural and mechanical capabilities of a polymer may be significantly reduced as such polymer is loaded with a drug. A previously devised solution to such dilemma has therefore been the coating of a stent""s metallic structure with a drug carrying polymer material in order to provide a stent capable of both supporting adequate mechanical loads as well as carrying and delivering drugs.
Various pharmacological agents have previously been employed to reduce or suppress thrombogenesis and various methods have been developed to load such pharmacological agents onto a stent in order to achieve the desired therapeutic effect. However, further improvement is desired both in terms of the anti-thrombogenic efficacy of materials that can be coated onto stents as well as the methods by which such materials are coated onto the stent.
The present invention overcomes the shortcomings of the prior art methods for imparting anti-thrombogenic characteristics to an implantable stent and more particularly provides a new method for coating a new anti-thrombogenic agent onto a stent. The resulting stent is deployed at the treatment site to simultaneously provide mechanical support to the lumen wall as well as to prevent thrombogenesis.
The method of the present invention requires the sequential application to a stent of a base layer and a biologically active top layer. The base layer preferably consists of a fluorocarbon coating while the active layer consists of a coating of glycocalyx or glycocalyx-like material. The fluorocarbon coating provides a sterile and carbon-rich substrate to attract and retain the glycocalyx material which in turn prevents the adhesion of proteins thereto. Glycocalyx is a naturally occurring substance that is found in the external region of the cell membrane in cells that line the walls of veins and arteries. The glycocalyx is dominated by glycosylated molecules, which direct specific interactions such as cell-cell recognition and contribute to the stearic repulsion that prevents undesirable non-specific adhesion of other molecules and cells. Bioengineered glycocalyx-like material mimics the biological characteristics of naturally occurring glycocalyx. The glycocalyx molecule as well as the molecules of bioengineered glycocalyx-type materials have a flexible backbone with two types of side chains, a sugar chain that has the anti-clotting properties and a water repellent chain. The water repellent chain attaches to the fluorocarbon coating and the sugar chain protrudes outwardly to form a dense layer that prevents the attachment of plasma proteins thereto.
These and other features and advantages of the present invention will become apparent from the following detailed description of preferred embodiments which illustrate by way of example the principles of the invention.